Kawasaki Disease (KD) is an acute, potentially fatal vasculitis of young children which predominately affects the coronary arteries. KD affects children of all nations and ethnic groups, and has replaced acute rheumatic fever as the most common cause of acquired heart disease in children in the U.S. and Japan. At Children's Memorial Hospital in Chicago alone, 65 new acute KD cases were diagnosed in 1998. Despite the fact that KD has become a significant pediatric problem in the U.S. the etiology and pathogenesis remain undefined. Our long-term objective is to determine the pathogenesis of KD. The overall goal of this proposal is to investigate the role of IgA and IgA plasma cells in the development of KD vasculitis. Recent studies from our laboratory indicate that IgA1 plasma cells infiltrate the vascular wall in acute KD. Preliminary data indicate that IgA genes in the vascular wall in acute KD are oligoclonal, suggesting that the IgA response in KD is directed toward specific antigens, either those of the potential pathogen(s) causing the illness, or host antigens by a molecular mimicry mechanism. Preliminary data also indicate that IgA plasma cells are present in markedly increased numbers in the respiratory and GI tracts of KD patients when compared with age-matched controls. Other preliminary data indicate that serum IgA1 in acute KD sera is aberrently glycosylated and therefore is likely to have altered properties. Our hypothesis is that KD is an immune-mediated vasculitis triggered by a mucosal pathogen, and that IgA plays a prominent role in pathogenesis. We propose to determine whether an oligoclonal IgA response is characteristic of KD. We will also determine glycosylation profiles of IgA l in KD sera. We will determine the distribution of IgA plasma cells in KD tissues using our established tissue repository of acute fatal KD cases. We will also characterize glycosylation profiles of IgA in the infiltrating plasma cells and determine whether these plasma cells produce matrix metalloproteinases (MMPs), matrix-degrading enzymes that participate in abdominal aortic aneurysm formation and that are produced by plasma cells in inflammatory diseases. These studies will elucidate the role of IgA and IgA plasma cells in the pathogenesis of KD, and will have important implications for potential diagnostic and treatment strategies for this increasingly recognized, potentially fatal childhood illness.